Sulfamides

ABSTRACT

Para-Sulfamidophenethanolamines are prepared from parasulfamidophenacyl halides. The phenethanolamines have useful beta-adrenergic blocking action.

Comer et al.

Dec. 2, 1975 SULFAMIDES [75] Inventors: William T. Comer; John D. Catt,

both of Evansville, ind.

[73] Assignee: Mead Johnson & Company,

Evansville, lnd.

[22] Filed: Sept. 20, 1973 [21] Appl. No.: 399,024

[52] U.S. Cl. 260/556 N; 260/243 B; 260/247.l R; 260/293.73; 260/326.5 SF; 424/246; 424/248; 424/267; 424/274; 424/321 [51] Int. Cl. C07C 143/76 [58] Field of Search 260/556 N, 556 A, 293.73, 260/247.1 R, 326.5 SF

[561 References Cited UNITED STATES PATENTS 3.711.545 l/l973 Kaiser et al 260/556 N OTHER PUBLICATIONS J. Med. Chem. 9:88-97, (1966), Uloth et al.

J. Med. Chem. 10:462-472. (1967). Larsen et al.

Primary ExaminerSherman D. Winters Attorney, Agent, or Firm-R. E. Carnaham; R. H. Uloth 57] ABSTRACT Para-Sulfamidophenethanolamines are prepared from para-sulfamidophenacyl halides. The phenethanolamines have useful beta-adrenergic blocking action.

11 Claims, N0 Drawings SULFAMIDES FIELD OF THE INVENTION This invention is concerned with a novel group of carbocyclic amides of sulfonic acid. Specifically, they are phenethanolamines bearing a sulfamide group on the benzene ring.

DESCRIPTION OF THE PRIOR ART Various arylalkylsulfamides, aryloxyalkylsulfamides, indanylsulfamides, and sulfamylaminomethylene malonates have been described in the literature as being useful as synthetic medicinals. The utilities of these prior substances lie almost exclusively in their action on the central nervous system including tranquilizer, sedative, and anticonvulsant action. None of these substances is a phenethanolamine bearing a sulfamido group on the benzene ring, nor do they have utility as adrenergic blocking agents. Refer for example to U.S. Pat. Nos. 3,143,549, 3,373,184, 3,383,414, and 3,406,174. Some sulfonanilides in the phenethanolamine series are described in U.S. Pat. No. 3,341,584.

SUMMARY OF THE INVENTION This invention is concerned with a novel group of sulfamides having the following structural formula NSO, CHOl-ICIINIIR" R Formula I and the pharmaceutically acceptable acid addition and metal salts thereof. In this formula, the following definitions are intended for the substituents referred to by the symbols R, R R and R. R is hydrogen, lower alkyl having from 1 to 4 carbon atoms, cyclopropyl, phenyl, or tolyl. R is hydrogen, lower alkyl having from 1 to 4 carbon atoms, cyclopropyl, or benzyl. R and R may be connected to one another or through an oxygen or sulfur atom to form with the sulfamide nitrogen atom a five or six membered heterocyclic group such as piperidine, pyrrolidine, or morpholine. R is hydrogen, methyl, or ethyl. R is hydrogen, cyclopropyl, or lower alkyl having from 1 to 4 carbon atoms.

In the foregoing definitions, the lower alkyl group referred to as having from 1 to 4 carbon atoms may have a straight or branched chain illustrated by methyl, ethyl, n-propyl, isopropyl, tert.-butyl, sec.-butyl, and isobutyl. Preferred compounds are those in which R and R are hydrogen or methyl, R is hydrogen, and R is a branched chain alkyl group having 3 or 4 carbon atoms such as isopropyl or tert.-butyl.

The compounds of this invention have adrenergic blocking action which is selective for the beta-adrenergic receptors, and reduce blood pressure when administered systemically to mammals. beta-Adrenergic blocking agents have been used in the treatment of various forms of heart disease including angina pectoris, arrhythmias, and hypertension, and have also been suggested for the treatment of anxiety neurosis and metabolic disorders such as hyperlactacidemia, hyperglycemia, and ketosis. Preferred compounds of the present 2 invention are those substances of the above formula wherein R is isopropyl and R R and R are either hydrogen or methyl.

The most preferred compounds are N,N-dimethyl- N-4-( l-hydroxy-2-isopropylaminoethyl)phenyl sulfamide and N- 4-(1-hydroxy-2-isopropylaminoethyl)phenyl sulfamide and the pharmaceutically acceptable acid addition salts thereof due to their high level of activity. The former sulfamide is particularly preferred since its beta-adrenergic blocking action is relatively selective for cardiac and smooth muscle as opposed to the metabolic effects of anti-hyperglycemia and anti-hyperlactacidemia. A relative specificity for antagonism of the effects of beta-adrenergic agonists on the peripheral vasculature is displayed by this compound as compared to that on the heart. It is a potent anti-arrhythmic agent having 2.6 times the'potency of procainamide and 1.3 times the potency of quinidine. The latter sulfamide exhibits the converse specificity in that it is a relatively stronger antagonist of the direct cardiac stimulatory effects evoked by beta-adrenergic agonists than of the peripheral vascular smooth muscle, and the hypotension caused thereby.

The compounds of Formula I in which R is hydrogen are useful as intermediates for the preparation of the compounds of Formula I wherein R" is lower alkyl. The compounds of Formula I wherein R or R is tert.-butyl are useful as intermediates for the preparation of compounds of Formula I wherein R or R is hydrogen.

DETAILED DESCRIPTION OF THE INVENTION The starting materials for the preparation of the compounds of the present invention are paraaminoacetophenone, para-aminopropiophenone, and para-aminobutyrophenone when R of Formula I is to be respectively hydrogen, methyl, or ethyl. These compounds are acylated with the appropriate R R N-substituted sulfamoyl halide or azide to yield the para-sulfamidophenone corresponding to the aminophenone starting material. The sulfamidophenone is then halogenated under conditions known to favor side chain halogenation as opposed to nuclear halogenation to provide the corresponding sulfamidophenacyl halide. The latter is then allowed to react with an N-benzyl-R -substituted amine to provide a compound of the formula N-SO; a

Formula II which on hydrogenation yields the compound of the present invention through cleavage of the N-benzyl group and reduction of the carbonyl group to a carbinol group.

Alternatively, the sulfamidophenacyl halide intermediate referred to above may be allowed to react with hexamethylenetetramine to provide a reaction complex which on hydrolysis in aqueous acid yields a sulfamidophenacylamine which after reduction of the carbonyl group to a carbinol group affords one of the compounds of the present invention wherein R, R and R are as defined in Formula I and R is hydrogen. Other methods for the synthesis of primary amines from alkyl halides such as reaction with potassium phthalimide may also be used.

The primary amines (Formula I, R is 1-1) have the medicinal utilities referred to above and are also useful as intermediates for the production of other compounds of the present invention in which R is lower alkyl having from 1 to 4 carbon atoms. The R substituents are introduced by conventional means such as by reductive alkylation using an alkylaldehyde or ketone having from 1 to 4 carbon atoms.

When it is desired to prepare one of the substances of the present invention wherein either R or R or both of them is a hydrogen atom, an N-tert.-butyl substituted sulfamoyl halide or azide is used as the acylating agent for the para-aminophenone in the first step of the process. This results in the production of a compound of the above formula in which R or R is tert.-butyl. The tert.-butyl group is readily removed by contacting the tert.-butylsulfamide with trifluoroacetic acid.

The depressor and beta-adrenergic blocking actions of the present substances may be demonstrated by conventional pharmacologic techniques. For example, the depressor response is evident when from 1 to mg./kg. of body weight of one of the substances of Formula I is injected intravenously into the anesthetized dog. The beta-adrenergic blocking action is evident in vitro when the isolated guinea pig trachea is cut into a spiral strip and suspended in a bath containing oxygenated Tyrodes solution and caused to relax by addition of a beta-adrenergic agonist such as isoproterenol to the bath. The relaxation brought about by the agonist is prevented by the prior addition of one of the present substances to the bath. The beta-adrenergic blocking action can be demonstrated in vivo in dogs anesthetized and surgically arranged for the recording of right ventricular contractile force, heart rate and blood pressure. beta-Adrenergic agonists such as isoproterenol cause an increase in heart rate and contractile force, and a decrease in blood pressure which can be prevented by prior treatment of the animal with one of the substances of the present invention.

The compounds of Formula I have exceedingly low toxicities. The LD values measured in mice treated orally are in the range of 1 to 2 grams per kilogram of body weight. Effective intravenous doses in dogs are in the range of from 0.1 to 10 mg./kg. of body weight. For therapeutic use, they may be administered by the oral or parenteral routes in doses ranging from 0.1 to 100 mg./kg. of body weight.

The term pharmaceutically acceptable which has been used with reference to the acid addition and metal salts of the compounds of Formula 1 refers to such salts in which the anionic portion of the acid addition salt or the cationic portion of the metal salt does not contribute significantly to the toxicity of the compound nor interfere with its therapeutic and pharmaceutical application. Examples of pharmaceutically acceptable acid addition salts include the hydrochloride, hydrobromide, acetate, propionate, phosphate, nitrate, succinate, gluconate, mucate, sulfate, methanesulfonate, ethanesulfonate, p-toluenesulfonate, etc. salts. Pharmaceutically acceptable metal salts include the sodium, potassium, lithium, magnesium, calcium, barium, zinc, and aluminum salts. The sulfamide free bases of Formula I are also pharmaceutically acceptable forms.

DESCRIPTION OF SPECIFIC EMBODIMENTS The nuclear magnetic spectral data reported below includes the chemical shifts (8) in parts per million, the multiplicity for that shift including the coupling constant (J value) when appropriate, and the relative area under the curve for each chemical shift which corresponds to the number of protons. The multiplicity symbols are: s, singlet; d, doublet; dd, doublet of doublets; bs, broad singlet; m, multiplet; and bm, broad multiplet. When deuterated dimethylsulfoxide (DMSO-d was used as solvent, the internal reference was tetramethylsilane. When deuterated water (D 0) was used as solvent, it served as the reference (l-IDO peak at 4.70 pp With respect to the infrared spectral data reported, only the principle peaks having specific structural significance are listed.

PROCEDURE 1 N-(4Acetylphenyl)-N ,l l 'dimethylsulfamide.

Dimethylsulfamoyl chloride (14.4 g., 0.10 mole) is added dropwise to p-arninoacetophenone (13.5 g., 0.10 mole) in pyridine (60 ml.) at lO15C. The mixture is stirred at room temperature overnight and then added to excess 6N l-ICL to give 14.1 g. (58%) of solid. The solid is dissolved in base, treated with charcoal, reprecipitated with dil. i-ICl, and recrystallized from water-isopropanol to give 8.9 g. (37%) of the above pure intermediate, m.p. 129l30C.

The foregoing procedure is adapted for use with other N,N-disubstituted sulfamoyl halides such as diethylsulfamoyl chloride, and methyl-tert.-butylsulfamoyl chloride. The following may be specifically prepared.

N-(4-Acetylphenyl)-N-benZyl-N-methylsulfamide.

4'-Acetyll -piperidinesulfonanilide.

4 -Acetyl-1-morpholinesulfonanilide 4 '-Acetyl-1-pyrrolidinesulfonanilide 4 '-Acetyl-1 -thiamorpholinesulfonanilide.

Similarly, p-aminopropiophenone and paminobutyrophenone may be substituted for paminoacetophenone in Procedure 1 to provide N,N- dimethyl-N'-(4-propionylphenyl)sulfamide and N,N- dimethyl-N'-(4-N-butyrylphenyl)sulfamide respectively.

PROCEDURE 2.

N( 4-Acetylphenyl )-N '-methylsulfamide.

Methylsulfamoyl chloride (42.5 g., 0.33 mole) is added dropwise to a mixture of triethylamine (33.4 g., 0.33 mole) and p-aminoacetophenone (40.5 g., 0.30 mole) in ether (1.5 1.) at 50C. The mixture is stirred at 50C. and then allowed to warm to -10C. The mixture if filtered to give a mixture of product and triethylamine hydrochloride. Washing with water and recrystallization from isopropanol furnishes 30.6 (40%) of the above pure intermediate, m.p. l59-159.5C. (dec.).

This method is particularly useful with N-monosubstituted sulfamoyl halides. Others which may advantageously be prepared in this fashion are N-(4-acetylphenyl)-N-tert.-butylsulfamide, N-(4-acetylphenyl)- N'-ethylsulfamide, and N-(4-acetylphenyl)-N'-cyclopropylsulfamide.

PROCEDURE 3.

N-(4-Acetylpheny-N 4-tolyl)sulfamide.

A solution of p-aminoacetophenone (3.65 g., 0.027 mole) in acetonitrile (50 ml.) is added dropwise to the triethylamine salt of p-toluenesulfamoylazide (0.027 mole) in acetonitrile (100 ml.). The solution is stirred for 2 days at room temperature and then concentrated in vacuo. The residue is dissolved in methylene chloride and, upon standing, yields 3 g. of the above intermediate. Another 2.2 g. may be obtained from the mother liquor. The combined crops are washed with water and recrystallized from isopropanol-heptane to yield the pure intermediate, m.p. 169.5170C. (dec.).

Other arylsulfamoyl azides may be substituted for ptoluenesulfamoylazide in the foregoing procedure. For example, benzenesulfamoylazide may be employed to provide N-(4-acetylphenyl)-N-phenylsulfamide.

PROCEDURE 4.

N-[4-(Bromoacetyl)phenyl]-N-tert.-butylsulfamide.

A few drops of bromine (from a total of 10.3 g., 0.064 mole) is added to N-(4-acetylphenyl)-N'-tert. butylsulfamide (17.3 g., 0.064 mole) in dioxane (200 ml.) solution at 15C. and the solution is stirred until the color is discharged. The remainder of the bromine is added during 5 min. and the solution is stirred for an additional min. thereafter. The solution is concentrated in vacuo and the residue triturated with isopropyl ether to give 20.7 g. (92%) of intermediate, recrystallized from isopropanol, m.p. 160.5-161C. (dec.).

This method is applicable to each of the other 4-acylphenylsulfamides mentioned in connection with the foregoing procedures. In the case of the propiophenone and butyrophenone intermediates, bromination takes place on the aliphatic carbon atom adjacent to the carbonyl group to yield N-[4-(a-bromopropionyl)phenyl]- N,N'-dimethylsu1famide, and N-[4-(a-bromobutyryl)- phenyl]-N',N'-dimethylsulfamide. Specifically, the following intermediates may be prepared by this method.

N-[4-(Bromoacetyl)phenyl]-N'-methylsulfamide N 4-( Bromoacetyl )phe nyl -N '-ethylsulfamide mide N-Benzyl-N-[4-(bromoacetyl)phenyll-N-methylsulfamide 4 -Bromoacetyl-1-piperidinesulfonanilide 4 '-Bromoacetyll -morpholinesulfonanilide 4 -Bromoacetyll -pyrrolidinesulfonanilide 4 '-Bromoacetyl-1-thiamorpholinesulfonanilide N-[4(Bromoacetyl)phenyl]-N-(4-tolyl)sulfamide para-toluenesulfonate N-[4-(Bromoacetyl)phenyl]-N-phenylsulfamide N-[4-(Bromoacetyl)phenyl]-N',N-dimethylsulfamide PROCEDURE 5.

N,N-Dimethyl-N 4-glycylphenyl )sulfamide Hydrochloride.

N-[4-(Bromoacetyl)phenyl]-N,N'-dimethylsulfamide (32 g., 0.10 mole) is added dropwise to a chloroform solution of hexamethylenetetramine (21.0 g., 0.15 mole) and the mixture is stirred overnight to give 42.6 g. of the complex. This is hydrolyzed by heating 0.5 hr. with 40 ml. conc. l-lCl and 500 ml. abs. ethanol. The mixture is cooled and the insoluble ammonium chloride is removed. The solution is concentrated in vacuo and the residue is triturated with isopropanol to give 27.3 g. of intermediate which is washed with water and recrystallized from methanol-isopropyl ether, m.p. l59l59.5C. (dec.).

Procedure 5 is applicable to the other 4- bromoacetylphenylsulfamide intermediates referred to in the foregoing procedures, and specifically the following may be prepared.

N-Benzyl-N-methyl-N-(4-glycylphenyl)sulfamide para-toluenesulfonate 4'-Glycyl-1-piperidinesulfonanilide para-toluenesulfonate 4-Glycyl-l-morpholinesulfonanilide para-toluenesulfonate 4'-Glycyl-1-pyrrolidinesulfonanilide para-toluenesulfonate 4 '-Glycyll -thiamorpholinesulfonanilide para-toluenesulfonate N-[4-(a-Aminopropionyl )phenyl]-N ',N -dimethylsulfamide N-[4-(a-Aminobutyryl)phenyl]-N',N-dimethylsulfamide.

PROCEDURE 6.

N-[4-( N-benzyl-N-isopropylglycyl)phenyl]-N'-tert.- butylsulfamide Hydrobromide.

The intermediate of Procedure 4 (10.0 g., 0.029 mole) is added portion-wise to an acetone solution (100 ml.) of benzylisopropylamine (9.0 g., 0.06 mole). The mixture is stirred for 5 hr. and then diluted with ether (400 ml.) to precipitate 4.9 g. of insoluble byproduct benzylisopropylamine hydrobromide which is filtered and discarded. The filtrate is acidified with ethanolic hydrogen bromide to yield 13 g. (89%) of desired intermediate recrystallized from 95% ethanol, m.p. 195.5196.5C. (dec.).

The following substances are prepared in the fashion described in Procedure 6.

methylsulfamide hydrobromide.

tolyl)sulfamide para-toluenesulfonate phenylsulfamide N-[4-(N-Benzyl-N-isopropylglycyl)phenyl]sulfamide para-toluenesulfonate sulfamide hydrobromide cyclopropylsulfamide hydrobromide By substitution of tert.-butylamine, sec.-butylamine, and cyclopropylamine for benzylpropylamine in the method of Procedure 6, N-[4-(N-tert.-butylglycyl)- phenyl]-N'-tert.-butylsulfamide hydrobromide, N-[4- (N-'sec.-butylglycyl)phenyl]-N'-tert.-butylsulfamide hydrobromide, and N-[4-(N-cyclopropylglycyl)- phenyl]-N-tert.-butylsulfamide hydrobromide are prepared.

PROCEDURE 7.

N-(4-Bromoacetyl)phenylsulfamide.

N-(4-Bromoacetylphenyl)-N'-tert.-butylsulfamide (7.6 g., 0.022 mole) is dissolved in ml. of trifluoroacetic acid and the solution is stirred for 5 hr. The solvent is then evaporated to yield 6.2 g. (96%) of the de- 7 sired intermediate, m.p. 160.5161C. (dec.), after recrystallization from acetonitrile.

PROCEDURE 8.

N-[4-(1-Hydroxy-2-isopropylaminoethyl)phenyl]N'- methylsulfamide Hydrobromide.

A suspension of N-[4-(N-benzyl-N-isopropylglycy1)- phenyl]-N'-methylsulfamide hydrobromide, 8.2 g., (0.018 mole) in 100 ml. of 90% aqueous ethanol is hydrogenated over palladium-on-charcoal catalyst at atmospheric pressure. When absorption of hydrogen has been completed, the catalyst is removed and the solvent is evaporated in vacuo to yield 6.1 g. of the desired product, recrystallized from ethanol-isopropyl ether, m.p. l66l68C. (corr.).

Anal. Found: C, 39.06; H, 6.02; N, 11.11 which corresponds to the molecular formula C H N O SHBr.

Nuclear magnetic resonance, DMSO-d 8(ppm): 1.31 [d (6.6Hz), 6H]; 2.58 [s, 3H]; 3.24 [m, 2H]; 3.49 [septet (6.6Hz), 1H]; 5.02 [dd (6.0, and 7.1Hz), 1H]; and 7.37 [m, 4H].

Infrared (pelletized with KBr): 815, 1070, 1160, 1330, 1380, 1390, 1450, 1510, 1595, 2720, 2820, 2980, 3220, and 3280 cm.

Listed below are a number of additional products which may be prepared according to Procedure 8. Along with the name of the product, the melting point, recrystallization solvent, and other characterizing data is given. The intermediate from which each was prepared is also listed.

N,N-Dimethyl-N'-[4-(2-amino- 1 -hydroxyethyl phenyl]sulfamide paraToluenesulfonate.

Melting point, 182.5-183.5C. (dec.)(corr.); recrystallized from 95% ethanol-isopropyl ether. Anal. Found: C, 47.08; H, 5.84; N, 9.69; which corresponds to the molecular formula C H ,N O -C H O S.

Nuclear magnetic resonance, D 0, 8(ppm): 2.29 [s, 3H]; 2.74 [s, 6H]; 3.17 [m, 2H]; 4.95 [dd (5.4, 7.4Hz), 1H]; 7.37 [m, 8H].

Infrared (pelletized with KBr); 815, 1150, 1 185, 1345, 1400, 1470, 1515, 1615, 2970, and 3180 cm. Prepared from N,N-dimethyl-N-(4-glycylphenyl)sulfamide hydrochloride.

N-[4-(2-Amino-1-hydroxyethy1)pheny1]-N-benzyl-N- methylsulfamide para-Toluenesulfonate.

Melting point, 152-153C. (corr); recrystallized from isopropanol-isopropyl ether.

Anal. Found: C, 54.66; H, 5.61; N, 8.26; which corresponds to the molecular formula C H ,N O -C H O S.

Nuclear magnetic resonance, DMSO-d 8(ppm): 2.30 [s, 3H]; 2.59 [s, 3H]; 2.93 [m, 2H]; 4.27 [s, 2H]; 4.79[m,1H];6.02[bs,1H];7.32[m,16H].

Infrared (pelletized with KBr): 690, 770, 820, 1130, 1160, 1220, 1340, 1520, 1620, 3100 cm.". Prepared from N-benzyl-N-(4-glycy1phenyl)-N-methylsulfamide para-toluenesulfonate.

4 '-(2-Amino-1-hydroxyethyl)-l-piperidinesulfonanilide para-toluenesulfonate.

Melting point, l68169C. (dec.)(corr.), recrystallized from 95% ethanol-isopropyl ether. Anal. Found:

C, 51.04; H, 6.19; N, 13.40; which corresponds to the molecular formula C H N O S'C H O S.

Nuclear magnetic resonance, DMSO-d 6(ppm): 1.43 [m, 6H]; 2.29 [s, 3H]; 3.09 [m, 6H]; 4.76 [m, 1H];5.93[bs,1H];'7.33[m, 8H]; 7.90 [bs, 3H]; 6.17 [s, 1H].

Infrared (pelletized with KBr): 810, 1230-1120, 1340, 1510, 1610, 2860, 2940, 3140, 3300 emf. Prepared from 4-glycyl-1-piperidenesulfonanilide para-toluenesulfonate.

N-tert.-Butyl-N -[4-(1-hydroxy-2-isopropylaminoethyl)phenyl]sulfamide Hydrobromide.

Melting point 182C. (dec.)(corr.), recrystallized from ethanol. Anal. Found: C, 44.20; H, 6.84; N, 10.11; which corresponds to the molecular formula C15H27N303S'HBI'.

Nuclear magnetic resonance, D 0, 6(ppm): 1.18 [s, 94H]; 1.29 [d (6.6Hz), 6H]; 3.23 [m, 2H]; 3.48 [septet (6.6Hz), 1H]; 5.00 [dd (6.0, 7.2Hz), 1H]; 7.51 [m, 4H].

Infrared (pelletized with KBr): 840, 1145, 1330, 1395, 1520, 1615, 2800, 2980, 3160, 3300 cm.. Prepared from N-[4-(N-benzy1-N-isopropylglycyl)- phenyll-N'-tert.-butylsulfamide hydrobromide.

N-[4-( 1-Hydroxy-2-isopropylaminoethyl)phenyl]sulfamide para-Toluenesulfonate.

Melting point 159160C. (corr.), recrystallized from absolute ethanol-isopropyl ether. Anal. Found: C, 48.79; H, 6.18; N, 9.34; which corresponds to the molecular formula C1 H 9N3O S'C7HgO3S.

Nuclear magnetic resonance, DMSO-d 8(ppm): [1.23 d(6.5Hz), 6H]; 2.30 [s, 3H]; 3.10 [m, 3H]; 4.85 [m, 1H]; 6.04 [bs, 1H]; 7.30 [m, 10H]; 9.25 [bs, 2H]; 9.50[bs,1H].

Infrared (pelletized with KBr): 820, 1160, 1330, 1400, 1520, 1620, 3160, 3230 emf. Prepared from N- 4-(N-benzyl-N-isopropylglycyl)phenyl sulfamide paratoluenesulfonate.

N-[4-( 1Hydroxy-2-isopropylaminoethyl)phenyl]-N'- (4-tolyl)sulfamide para-Toluenesulfonate.

Melting point 164.5165.5C. (corr.) recrystallized.

from absolute ethanol. Anal. Found: C, 56.1 1; H, 6.11; N, 7.63; which corresponds to the molecular formula C15H25N303S'C1H502S.

Nuclear magnetic resonance, DMSO-d 6(ppm): 1.22 [d (6.5Hz), 6H]; 2.21 [s, 3H]; 2.30 [s, 3H]; 3.15 [m, 3H];4.85 [m,1H];6.05[bs,1H];7.30[m,12H]; 9.83 [bm, 4H].

Infrared (pelletized with KBr): 820, 1 160, 1220, 1340, 1400, 1520, 1620, 2870, 2960, 3180 cm.". Prepared from N-[4-(N-benzyl-N-isopropylglycyl)phenyl -N'-(4-tolyl)sulfamide para-toluenesulfonate.

Procedure 8 is also applicable to the preparation of N,N-dimethyl-N-[4-( 1-hydroxy-2-aminopropyl)- phenyl]sulfamide, and N,N-dimethyl-N'-[4-( 1- hydroxy-Z-aminobutyl)pheny1]su1famide respectively from N-[4-(a-aminopropionyl)phenyll-N',N'-dimethylsulfamide, and N-[4-(a-aminobutyryl)phenyl]-N',- N'-dimethylsulfamide. Similarly, N-[4-(1-hydroxy-2- isopropylaminoethyl)phenyl]-N'-pheny1sulfamide may be prepared from N-[4-(N-benzyl-N-isopropylglycyl)- phenyl]-N'-phenylsulfamide.

Other sulfamidophenethanolamines which may be prepared by Procedure 8 from intermediates described herein are:

4'-( 2-Amino- 1 -hydroXyethyl)-1 -morpholinesu1- fonanilide para-toluenesulfonate 9 4-(2-Amino-1-hydroxyethyl)-l-pyrrolidinesulfonanilide para-toluenesulfonate 4 2-Amino-l -hydroxyethyl)- l -thiamorpholine para-toluenesulfonate N-tert.-Butyl-N'-[4-( 1-hydroxy-2-cyclopropylaminoethyl)phenyl]-sulfamide hydrobromide N-tert.-Butyl-N-[4-( l-hydroxy-2-tert.-butylam'inoethyl)phenyl]sulfamide hydrobromide N-tert.-Butyl-N -[4-( l-hydroxy-2-sec.-butylaminoethyl)phenyl]sulfamide hydrobromide PROCEDURE 9.

N-BenzyLN '-[4-( 1-hydroxy-2-isopropylaminoethyl)- phenyl]-N-methylsulfamide.

N'- 4-( Z-Aminol -hydroxyethyl)phenyl -N-benzyl- N-methylsulfamide para-toluenesulfonate, 0.021 mole, is converted to the free base by treatment with aqueous sodium hydroxide and extraction with ether. The ether extract is evaporated and the residue is dissolved in 100 ml. of ethanol and treated with 0.021 mole of acetic acid thus providing the acetate salt of the starting material. Acetone, 0.06 mole, is added to the solution which is then reduced at a pressure of 45 psig. with hydrogen over a platinum oxide catalyst. When hydrogen absorption ceases, the catalyst is removed and the reaction solvent is distilled in vacuo. The residue is treated with aqueous sodium bicarbonate and the mixture extracted with methylene chloride. The dried extracts are concentrated in vacuo and the residue triturated with ether to yield 6.2 g. of the desired product which is recrystallized from isopropanolisopropyl ether, m.p. 131.5-l34.5C. (corr.).

Anal. Found: C, 60.44; H, 7.44; N, 11.17.

Nuclear magnetic resonance, DMSO-d 8(ppm):

0.99 [d (6.2 Hz), 6H]; 2.60 [s, 3H]; 2.68 [m, 3H]; 4.26

[s, 2H]; 3.77 [dd (6.0, 7.0Hz), 1H]; 5.20 [bs, 3H]; 7.30 [m, 9H].

Infrared (pelletized with KBr): 695, 765, 840, 1150, 1340, 1380, 1395, 1452, 1510, 1610, 2860, 2920, 2960, 3120, 3280 cm".

The following substances were prepared according to Procedure 9. Along with the name of the product, the melting point, recrystallization solvent, and other characterizing data is listed. The intermediate from which each was prepared is also identified.

4-(2-lsopropylamino-1-hydroxyethyl)-1-piperidinesulfonanilide Hydrochloride.

Melting point 176l76.5C. (corr.) recrystallized from isopropanol-95% ethanol-isopropyl ether. Anal. Found: C, 50.56; H, 7.35; N, 1107.

Nuclear magnetic resonance, DMSO-d 8(ppm): 1.28 [d (6.5Hz)]; 1.43 [m, 12H when combined with preceding shift]; 3.09 [m, 7H]; 5.00 [m, 1H]; 6.08 [bs, 1H]; 7.28 [m, 4H]; 9.00 [bs, 1H]; 9.60 [bs, 1H]; 10.20 [s, 1H].

Infrared (pelletized with KBr): 840, 1055, 1145, 1340, 1405, 1470, 1520, 1620, 2860, 2950 cm.* .Prepared from 4 '-(2-amino-1-hydroxyethyl)-lpiperidinesulfonanilide para-toluenesulfonate.

N,N-Dimethyl-N-[4-(1-hydroxy-2-isopropylaminoethyl)phenyl]sulfamide Hydrochloride.

Melting point 182l83.5C. (corr.), recrystallized from ethanol-ethyl ether. Anal. Found: C, 45.94; H, 7.09; N, 12.16.

Nuclear magnetic resonance, D 0, 8(ppm): 1.36 [d (6.5Hz), 6H]; 2.80 [s, 6H]; 3.45 [m, 3H]; 5.07 [dd (6.0, 7.1Hz), 1H]; 7.40 [m, 4H].

Infrared (pelletized with KBr): 840, 1145, 1335, 1400, 1470, 1520, 1620, 2980, 3140 cm.*. Prepared from N,N-dimethyl-N-[4-(2-amino-1-hydroxyethyl)- phenyl]sulfamide para-toluenesulfonate.

What is claimed is:

l. A compound selected from the group consisting of substances having the formula wherein R is hydrogen, lower alkyl having from 1 to 4 carbon atoms, cyclopropyl, phenyl, or tolyl;

R is hydrogen, lower alkyl having from 1 to 4 carbon atoms, cyclopropyl, or benzyl; or

R and R are joined to form with the nitrogen atom to which they are attached the l-piperidyl group;

R is hydrogen, methyl, or ethyl; and

R is hydrogen, cyclopropyl, or lower alkyl having from 1 to 4 carbon atoms and the pharmaceutically acceptable acid addition and metal salts thereof.

2. The compound of claim 1 wherein R R and R are lower alkyl having from 1 to 4 carbon atoms and R is hydrogen.

3. The compound of claim 1 wherein R and R are methyl, R is hydrogen, and R is lower alkyl having from 1 to 4 carbon atoms.

4. The compound of claim 1 wherein R, R and R are hydrogen, and R is lower alkyl having from 1 to 4 carbon atoms.

5. The compound of claim 1 wherein R and R are methyl, R is hydrogen, and R is a branched chain alkyl group having 3 or 4 carbon atoms.

6. The compound of claim 1 wherein R R and R are hydrogen, and R is a branched chain alkyl group having 3 or 4 carbon atoms.

7. The compound of claim 1 wherein R is hydrogen, and R R and R are as defined in claim 1.

8. N,N-Dimethyl-N-[4-( l-hydroxy-Z-isopropylaminoethyl)-phenyl]sulfamide.

9. The hydrochloride salt of the compound of claim 8.

110. N-[4-( l-Hydroxy-2-isopropylaminoethyl)- phenyllsulfamide.

111. The p-toluene sulfonate salt of the compound of claim 10. 

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF SUBSTANCES HAVING THE FORMULA
 2. The compound of claim 1 wherein R1, R2, and R4 are lower alkyl having from 1 to 4 carbon atoms and R3 is hydrogen.
 3. The compound of claim 1 wherein R1 and R2 are methyl, R3 is hydrogen, and R4 is lower alkyl having from 1 to 4 carbon atoms.
 4. The compound of claim 1 wherein R1, R2, and R3 are hydrogen, and R4 is lower alkyl having from 1 to 4 carbon atoms.
 5. The compound of claim 1 wherein R1 and R2 are methyl, R3 is hydrogen, and R4 is a branched chain alkyl group having 3 or 4 carbon atoms.
 6. The compound of claim 1 wherein R1, R2, and R3 are hydrogen, and R4 is a branched chain alkyl group having 3 or 4 carbon atoms.
 7. The compound of claim 1 wherein R4 is hydrogen, and R1, R2, and R3 are as defined in claim
 1. 8. N,N-Dimethyl-N''-(4-(1-hydroxy-2-isopropylaminoethyl)-phenyl)sulfamide.
 9. The hydrochloride salt of the compound of claim
 8. 10. N-(4-(1-Hydroxy-2-isopropylaminoethyl)phenyl)sulfamide.
 11. The p-toluene sulfonate salt of the compound of claim
 10. 